Predicting outcomes of Lung Cancer using the modified glasgow prognostic score: A systematic review and meta-analysis

Background & Objective: Previous studies have suggested that the modified Glasgow Prognostic Score (mGPS) could be a potential biomarker for lung cancer (LC). However, the association between mGPS and overall survival (OS) or progression-free survival (PFS) in lung cancer patients remains unclear. The purpose of our study was to investigate possible correlation between mGPS and OS or PFS in LC patients. Methods: An extensive search of PubMed, Cochrane Library, EMbase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Trip Database, Worldwide Science, and Google Scholar databases was done for relevant articles, published prior to May 30, 2021, that report correlation between mGPS and OS or PFS in LC patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used as the main parameters for evaluation. Results: A total of 28 studies involving 9,748 lung cancer patients were analysed. The pooled analysis revealed that elevated mGPS (≥ 0) was associated with poor OS (HR=1.54; 95% CI, 1.32-1.77) and PFS (HR=1.49; 95% CI, 1.17-1.82). Furthermore, a significant correlation between mGPS (1 or 2) and OS was observed. However, no significant correlation was found between mGPS (1 or 2) and PFS. Subgroup analysis based on ethnicity demonstrated that mGPS ≥ 0 was associated with worse OS compared to mGPS=0 in both Asian (HR=1.46; 95% CI, 1.04-1.89; p<0.05) and Caucasian (HR=1.64; 95% CI, 1.35-1.94; p<0.05) cohorts of LC patients. Conclusions: Our results demonstrate that positive mGPS is associated with poor survival results. Therefore, mGPS may be used as a biomarker for predicting prognosis in LC patients.


INTRODUCTION
Lung cancer (LC) is the second most common cancer and a primary cause of cancer-related mortality worldwide. 1,2LC is often diagnosed at advanced stages, necessitating standard treatments like chemotherapy and surgery. 3,4Recent advancements in the computed tomography (CT) technology allowed to reduce mortality rates by 16 to 20% in patients with a history of smoking. 5Nevertheless, overall survival (OS) for lung cancer patients remains poor.While clinical staging is currently the most reliable prognostic factor for lung cancer, it provides limited information on individual disease progression.
Emerging evidence suggests a correlation between the increased systemic inflammation and the reduced survival rates in various cancer types.Studies have shown that the inflammatory state contributes to angiogenesis, cancer cell proliferation, tumour metastasis, and overall disease progression. 7,8Serum levels of albumin and C-reactive protein (CRP) serve as established markers for systemic inflammation and nutritional status, respectively. 9,10The modified Glasgow Prognostic Score (mGPS) that considers both levels of albumin and CRP, currently serves as a prognostic indicator for multiple cancers, including LC. [11][12][13][14] Patients with both hypoalbuminemia (<35 mg/L) and increased CRP (>10 mg/L) levels receive a score of Two.A score of One is assigned if either one of these abnormal values is present, while a score of 0 indicates the absence of both abnormalities.
Most studies investigating mGPS have primarily focused on patients who have undergone surgery or chemotherapy. 15,16Although there is a growing support of the clinical significance of mGPS at different stages of LC, [17][18][19][20][21][22][23][24] the available data is still scarce and inconsistent.Therefore, the predictive capacity of mGPS in lung cancer has not been definitively established.While a study by Jin et al. in 2017 attempted to compile data regarding the predictive efficacy of mGPS for LC, it included only eleven studies, which made the results of the subgroup analyses inconclusive. 25Therefore, there is an urgent need for more robust, simple, and easily measurable prognostic indicators to predict LC outcomes. 6Hence, the aim of our meta-analysis was to investigate the possible correlation between mGPS and OS or PFS in LC patients.

METHODS
The meta-analysis was carried out in accordance with the guidelines specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 26 and was registered with International Prospective Register of Systematic Reviews (PROSPERO) under the identification number CRD42021261007.
Inclusion criteria was published observational studies (prospective or retrospective cohort) investigating the correlation between mGPS and OS or PFS in lung cancer and the studies had patients with confirmed pathologically diagnosed lung cancer.Exclusion criteria were applied to studies that did not report relevant outcomes and those with unavailable full-texts.We performed a thorough search of PubMed, EMbase, Cochrane Library, Trip Database, Worldwide Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Google Scholar databases for relevant articles published up from Jan 1, 1956 to May 30, 2021.The search utilized various combinations of keywords such as "Pulmonary Neoplasms," "lung cancer," "Pulmonary Cancer," "C-Reactive Protein," "Albumin, Serum," "Prognosis," and "modified Glasgow prognosis score".For each study, two authors conducted independent data extraction that included first author's name, country of origin, ethnicity, year of publication, cohort type, study duration, patient count, treatment approaches, population characteristics, tumour node metastases (TNM) stage data, endpoints, and survival details.
Newcastle-Ottawa Quality Assessment Scale (NOS) 27 was used to assess the quality of the included studies.The NOS quality scores range from 0 (lowest) to 8 (highest) based on predetermined criteria.Funnel plot analysis 28 and Egger's regression test 29 were used to assess the publication bias.The survival endpoints for different mGPS scores were analysed using pooled hazard ratios (HRs) with 95% confidence intervals (CIs).Cochran's Q-test and I 2 -statistic were used to assess heterogeneity.Sensitivity analysis was done by excluding one study at a time from the pooled results to evaluate the robustness of the findings.STATA 12.0 software (Stata Corporation, College Station, TX, USA) was used for statistics.

RESULTS
A total of 596 records were identified.Of them, 321 remained after duplicates removal.Subsequently, irrelevant studies and review articles were excluded, leaving 82 articles for eligibility assessment.Finally, 28 studies met the eligibility criteria and were included in the meta-analysis.The literature selection process is illustrated in Fig. 1.

Study Characteristics:
Publication years of the studies ranged from 2010 to 2021, and the sample sizes varied from 24 to 1,745 LC patients.One publication was treated as two separate studies due to its coverage of two different cohorts (operative and nonoperative) and separate reporting of hazard ratios (HRs).22 Most studies were of good quality, with a Newcastle-Ottawa quality assessment scale (NOS) score of six or higher. Supplementary Table-

Sensitivity analysis and publication bias:
A sensitivity analysis was conducted by sequentially excluding one study at a time from the pooled results.The analysis demonstrated that the combined HRs for both OS and PFS did not exhibit significant variations, indicating the stability of the results.Egger's test indicated evidence of publication bias for the correlation between mGPS > 0 and OS (P<0.001).However, no publication bias was observed for the correlation between mGPS > 0 and PFS (P=0.57).

DISCUSSION
The results of our meta-analysis, which included 28 studies, indicate that an elevated mGPS is a predictive indicator of poor survival in LC patients.Subgroup analyses further supported the predictive effectiveness of mGPS for OS and PFS in lung cancer.Our findings suggest that mGPS may serve as a reliable and costeffective prognostic marker for LC.While previous meta-analysis have primarily focused on assessing the prognostic value of mGPS in relation to OS. 25 Our study represents the first meta-analysis to provide comprehensive pooled evidence regarding the prognostic value of mGPS for both OS and PFS in LC patients.
Inflammatory state plays a critical role in maintaining tumor microenvironment as it enables cancer cells to evade the immune system. 49Studies showed that inflammatory markers, such as the neutrophil/lymphocyte and platelet/lymphocyte ratios, have shown correlations with poor prognosis in certain solid malignancies. 7,15The modified Glasgow Prognostic Score takes into account both serum C-reactive protein (CRP) and albumin levels in clinical samples, 33,50 and reflects both the inflammatory and nutritional status of patients. 51Production of CRP, an acute-phase protein primarily produced by hepatocytes, is triggered by inflammation, tissue injury, and infection.][54][55][56] Similarly, hypoalbuminemia is linked to tumor progression and poor survival in lung cancer. 9,57urthermore, it has been observed that as CRP levels increase, albumin levels tend to decline in cancer patients, suggesting a connection between systemic inflammation and cachexia. 58It was shown in a recent study by Ran et al. (2022) that a number of factors affect the prognosis and survival of elderly patients with advanced NSCLC. 59Age, performance status score, smoking history, and style of treatment are some of these variables.It is essential to give efficient therapies in accordance with the tenets of evidence-based medicine in order to guarantee the best results.Similar to the previous study, Li et al. 60 further investigation on the treatment results of patients with advanced NSCLC and EGFR gene mutations.When compared to Gefitinib medication in this patient population, the study found that oxitinib treatment was linked with considerably longer PFS and a reduced risk of adverse events.These results highlight the significance of identifying the best therapeutic strategy for each patient based on their unique genetic traits and therapeutic response.
][63][64][65] For example, Nie et al. conducted an 11-study metaanalysis involving 2,830 patients and demonstrated that mGPS is a predictor of poor OS and PFS in gynecologic malignancies. 65Another study found that a positive mGPS is associated with lower OS and cancer-specific survival (CSS) in colorectal cancer. 66Additionally, a recent meta-analysis of 20 studies indicated that mGPS may independently predict outcomes in patients with urological cancer. 63Our results are consistent with these previous findings, providing further evidence that elevated mGPS can be used as a prognostic marker for OS in lung cancer.Future research efforts should focus on the development of specific prognostic models or nomograms that incorporate mGPS as a pivotal prognostic factor for LC.This personalized approach can significantly enhance prognosis assessment and guide treatment decisions more effectively.By integrating mGPS assessment and considering the specific needs of patients, healthcare providers can make more informed decisions, ultimately enhancing the patient's journey through diagnosis, treatment, and recovery.
Limitations of the study: Firstly, 19 out of 28 included studies were retrospective cohort studies, which may introduce inherent biases.Secondly, the participants in the included studies were at different stages of lung cancer progression, which could introduce variability in the results.Thirdly, due to limited data availability in the included studies, we were unable to develop a prognostic model specifically for patients with lung cancer.
Recommendation: Further studies should focus on the development of a specific predictive model or nomogram that incorporates the mGPS as a prognostic factor for lung cancer.This would provide a more comprehensive and personalized approach to prognosis assessment in LC patients.

CONCLUSION
We have shown that mGPS may serve as a useful biomarker for predicting prognosis in lung cancer patients, with a positive mGPS linked to poor survival.

Fig. 1 :
Fig.1: Flow diagram for the selection of studies and specific reasons for exclusion from the present meta-analysis.

Table - I
: Summary of estimates based on subgroup analysis for overall survival (OS) using mGPS in lung cancer patients.

Table -
II: Summary of estimates based on subgroup analysis for progression free survival (PFS) using mGPS in lung cancer patients.Supplementary Table-I: Characteristics of included studies in the meta-analysis investigating correlation of mGPS with OS and PFS in lung cancer patients.Not Reported; SBRT-Stereotactic body radiation therapy; TP-Time to Progression; ICIs-immune checkpoint inhibitors; mGPS-modified Glasgow prognostic score; NSCLC-Non-small cell lung Cancer; SCLC-Small cell lung Cancer; R-Reported in included article; E-Estimated from Kaplan Meir Curves.